SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT Ceftriaxone (as sodium) 500mg Powder for Injection * 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 500mg vial contains ceftriaxone sodium equivalent to 500mg of ceftriaxone. Each 500mg vial contains 41.5mg (1.8mmol) sodium. 3. PHARMACEUTICAL FORM Powder for solution for injection White or yellowish crystalline powder 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Ceftriaxone (as sodium) 500mg Powder for Injection is an antibiotic used in combination with other medicines in the treatment of Human Immunodeficiency Virus (HIV) related infections in adults, adolescents and children. Ceftriaxone (as sodium) 500mg Powder for Injection should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum ( see section 4.4). Consideration should be given to official guidelines on the appropriate use of antibacterial agents (e.g. those of WHO). 4.2 Posology and method of administration Posology The dose depends on the severity, susceptibility, site and type of infection and on the age and hepato-renal function of the patient. The doses recommended in the tables below are the generally recommended doses in these indications. In particularly severe cases, doses at the higher end of the recommended range should be considered. * Trade names are not prequalified by WHO. This is the national medicines regulatory authority's (NMRA) responsibility. Throughout this WHOPAR the proprietary name is given as an example only. 2

3 Adults and children over 12 years of age ( 50 kg) Ceftriaxone dosage* Treatment frequency** Indications 1-2g Once daily Community acquired pneumonia Acute exacerbations of chronic obstructive pulmonary disease Intra-abdominal infections 2g Once daily Hospital acquired pneumonia Complicated urinary tract infections ( including pyelonephritis) Complicated skin and soft tissue infections Infections of bones and joints 2-4g Once daily Management of neutropenic patients with fever that is suspected to be due to a bacterial infection Bacterial endocarditis Bacterial meningitis * In documented bacteraemia, the higher end of the recommended dose range should be considered. ** Twice daily (12 hourly) administration may be considered where doses greater than 2g daily are administered. Indications for adults and children over 12 years of age ( 50 kg) that require specific dosage schedules: Pre-operative prophylaxis of surgical site infections 2 g as a single pre-operative dose. Gonorrhoea 500 mg as a single intramuscular dose. Syphilis The generally recommended doses are 500 mg-1 g once daily increased to 2 g once daily for neurosyphilis for days. The dose recommendations in syphilis, including neurosyphilis, are based on limited data. Disseminated Lyme borreliosis (early [Stage II] and late [Stage III]) 2 g once daily for days. Paediatric population Neonates, infants and children 15 days to 12 years of age (< 50 kg) For children with bodyweight of 50 kg or more, the usual adult dosage should be given. 3

4 Ceftriaxone dosage* Treatment frequency** Indications 50-80mg/kg Once daily Intra-abdominal infections mg/kg (max 4g) mg/kg (max 4g) Once daily Once daily 100mg/kg(max 4g) Once daily Complicated urinary tract infections ( including pyelonephritis) Community acquired pneumonia Hospital acquired pneumonia Complicated skin and soft tissue infections Infections of bones and joints Management of neutropenic patients with fever that is suspected to be due to a bacterial infection Bacterial meningitis Bacterial endocarditis * In documented bacteraemia, the higher end of the recommended dose range should be considered. ** Twice daily (12 hourly) administration may be considered where doses greater than 2g daily are administered. Indications for neonates, infants and children 15 days to 12 years (< 50 kg) that require specific dosage schedules: Pre-operative prophylaxis of surgical site infections mg/kg as a single pre-operative dose. Syphilis The generally recommended doses are mg/kg (max 4 g) once daily for days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. Official guidance should be taken into consideration. Disseminated Lyme borreliosis (early [Stage II] and late [Stage III]) mg/kg once daily for days. The recommended treatment durations vary and national or local guidelines should be taken into consideration. 4

5 Neonates 0-14 days Ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age). Ceftriaxone dosage* Treatment frequency** Indications 20-50mg/kg Once daily Intra-abdominal infections Complicated skin and soft tissue infections Complicated urinary tract infections ( including pyelonephritis) Community acquired pneumonia Hospital acquired pneumonia Infections of bones and joints 50mg/kg Once daily Bacterial meningitis Management of neutropenic patients with fever that is suspected to be due to a bacterial infection Bacterial endocarditis * In documented bacteraemia, the higher end of the recommended dose range should be considered. A maximum daily dose of 50 mg/kg should not be exceeded. Indications for neonates 0-14 days that require specific dosage schedules: Pre-operative prophylaxis of surgical site infections mg/kg as a single pre-operative dose. Syphilis The generally recommended dose is 50 mg/kg once daily for days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. Official guidance should be taken into consideration. Duration of therapy The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of ceftriaxone should be continued for hours after the patient has become afebrile or evidence of bacterial eradication has been achieved. Older people The dosages recommended for adults require no modification in older people provided that renal and hepatic function is satisfactory. 5

6 Patients with hepatic impairment Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment provided renal function is not impaired. There are no study data in patients with severe hepatic impairment (see section 5.2). Patients with renal impairment In patients with impaired renal function, there is no need to reduce the dosage of ceftriaxone provided hepatic function is not impaired. Only in cases of preterminal renal failure (creatinine clearance < 10 ml/min) should the ceftriaxone dosage not exceed 2 g daily. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Ceftriaxone is not removed by peritoneal- or haemodialysis. Close clinical monitoring for safety and efficacy is advised. Patients with severe hepatic and renal impairment In patients with both severe renal and hepatic dysfunction, close clinical monitoring for safety and efficacy is advised. Method of administration Ceftriaxone can be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over 5 minutes, or by deep intramuscular injection. Intravenous intermittent injection should be given over 5 minutes preferably in larger veins. Intravenous doses of 50 mg/kg or more in infants and children up to 12 years of age should be given by infusion. In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see section 4.3 and 4.4). Intramuscular injections should be injected well within the bulk of a relatively large muscle and not more than 500mg should be injected at one site. Intramuscular administration should be considered when the intravenous route is not possible or less appropriate for the patient. For doses greater than 2 g intravenous administration should be used. If lidocaine is used as a solvent, the resulting solution should never be administered intravenously (see section 4.3). The information in the Summary of Product Characteristics of lidocaine should be considered. Ceftriaxone is contraindicated in neonates ( 28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition, because of the risk of precipitation of ceftriaxone-calcium (see section 4.3). Diluents containing calcium, (e.g. Ringer s solution or Hartmann s solution), should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2). For pre-operative prophylaxis of surgical site infections, ceftriaxone should be administered minutes prior to surgery. For instructions on reconstitution of the medicinal product before administration, see section

7 4.3 Contraindications Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients listed in section 6.1. History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems). Ceftriaxone is contraindicated in: Premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age) Full-term neonates (up to 28 days of age): - with hyperbilirubinaemia, jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired - if they require (or are expected to require) intravenous calcium treatment, or calcium-containing infusions due to the risk of precipitation of a ceftriaxone-calcium salt (see sections 4.4, 4.8 and 6.2). In vitro studies have shown that ceftriaxone can displace bilirubin from its serum albumin binding sites leading to a possible risk of bilirubin encephalopathy in these patients. Contraindications to lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine solution is used as a solvent (see section 4.4). See information in the Summary of Product Characteristics of lidocaine, especially contraindications. Ceftriaxone solutions containing lidocaine should never be administered intravenously. 4.4 Special warnings and special precautions for use Hypersensitivity reactions As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8). In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftriaxone is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents. Severe cutaneous adverse reactions (Stevens Johnson syndrome or Lyell s syndrome/toxic epidermal necrolysis) have been reported; however, the frequency of these events is not known (see section 4.8). Interaction with calcium containing products Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term neonates aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than neonates, treated with ceftriaxone and calciumcontaining solutions or any other calcium-containing products. In vitro studies demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups. In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calciumcontaining intravenous solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or 7

8 thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing total parenteral nutrition (TPN) solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion and the infusion lines flushed between solutions (see sections 4.3, 4.8, 5.2 and 6.2). Paediatric population Safety and effectiveness of Ceftriaxone in neonates, infants and children have been established for the dosages described under Posology and Method of Administration (see section 4.2). Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section 4.3). Immune mediated haemolytic anaemia An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Ceftriaxone (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during Ceftriaxone treatment in both adults and children. If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin-associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined. Long term treatment During prolonged treatment complete blood count should be performed at regular intervals. Colitis/Overgrowth of non-susceptible microorganisms Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftriaxone (see section 4.8). Discontinuation of therapy with ceftriaxone and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents. Severe renal and hepatic insufficiency In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacy is advised (see section 4.2). Interference with serological testing Interference with Coombs tests may occur, as Ceftriaxone may lead to false-positive test results. Ceftriaxone can also lead to false-positive test results for galactosaemia (see section 4.8). Non-enzymatic methods for the glucose determination in urine may give false-positive results. Urine glucose determination during therapy with Ceftriaxone should be done enzymatically (see section 4.8). 8

9 Sodium Each 500mg of Ceftriaxone contains 1.8 mmol sodium. This should be taken into consideration in patients on a controlled sodium diet. Antibacterial spectrum Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable for use as a single agent for the treatment of some types of infections unless the pathogen has already been confirmed (see section 4.2). In polymicrobial infections, where suspected pathogens include organisms resistant to ceftriaxone, administration of an additional antibiotic should be considered. Use of lidocaine In case a lidocaine solution is used as a solvent, ceftriaxone solutions must only be used for intramuscular injection. Contraindications to lidocaine, warnings and other relevant information as detailed in the Summary of Product Characteristics of lidocaine must be considered before use (see section 4.3). The lidocaine solution should never be administered intravenously. Biliary lithiasis When shadows are observed on sonograms, consideration should be given to the possibility of precipitates of calcium ceftriaxone. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder and have been observed more frequently at ceftriaxone doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of ceftriaxone therapy. Rarely precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of ceftriaxone treatment should be considered by the health care provider based on specific benefit risk assessment (see section 4.8). Biliary stasis Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with Ceftriaxone (see section 4.8). Most patients presented with risk factors for biliary stasis and biliary sludge e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor of Ceftrixone-related biliary precipitation cannot be ruled out. Renal lithiasis Cases of renal lithiasis have been reported, which is reversible upon discontinuation of ceftriaxone (see section 4.8). In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the health care provider based on specific benefit risk assessment. 9

10 4.5 Interaction with other medicinal products and other forms of interaction Calcium-containing diluents, such as Ringer s solution or Hartmann s solution, should not be used to reconstitute Ceftriaxone vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxonecalcium (see sections 4.2, 4.3, 4.4, 4.8 and 6.2). Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently and the posology of the anti-vitamin K drug adjusted accordingly, both during and after treatment with ceftriaxone (see section 4.8). There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins. The recommended monitoring of aminoglycoside levels (and renal function) in clinical practice should be closely adhered to in such cases. In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. The clinical relevance of this finding is unknown. There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (intravenous or oral). In patients treated with ceftriaxone, the Coombs' test may lead to false-positive test results. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine may yield false-positive results. For this reason, glucose level determination in urine during therapy with ceftriaxone should be carried out enzymatically. No impairment of renal function has been observed after concurrent administration of large doses of ceftriaxone and potent diuretics (e.g. furosemide). Simultaneous administration of probenecid does not reduce the elimination of ceftriaxone. 4.6 Pregnancy, Breastfeeding and Fertility Pregnancy Ceftriaxone crosses the placental barrier. There are limited amounts of data from the use of ceftriaxone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal development (see section 5.3). Ceftriaxone should only be administered during pregnancy and in particular in the first trimester of pregnancy if the benefit outweighs the risk. 10

11 Breastfeeding Ceftriaxone is excreted into human milk in low concentrations but at therapeutic doses of ceftriaxone no effects on the breastfed infants are anticipated. However, a risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded. The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility Reproductive studies have shown no evidence of adverse effects on male or female fertility. 4.7 Effects on ability to drive and use machines During treatment with ceftriaxone, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines (see section 4.8). Patients should be cautious when driving or operating machinery. 4.8 Undesirable effects The most frequently reported adverse reactions for ceftriaxone are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased. Data to determine the frequency of ceftriaxone ADRs was derived from clinical trials. The following convention has been used for the classification of frequency: Very common ( 1/10) Common ( 1/100 - < 1/10) Uncommon ( 1/ < 1/100) Rare ( 1/ < 1/1000) Not known (cannot be estimated from the available data) System Organ Class Common Uncommon Rare Not Known a Infections and infestations Genital fungal infection Pseudo-membranous Superinfection b colitis b Blood and lymphatic system disorders Eosinophilia, Leucopenia, Thrombocytopenia Granulocytopenia, Anaemia, Coagulopathy Haemolytic anaemia b, Agranulocytosis Immune system disorders Nervous system disorders Headache, Dizziness Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction, Hypersensitivity b Convulsion 11

12 System Organ Class Common Uncommon Rare Not Known a Ear and labyrinth disorders Vertigo Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Hepatobiliary disorders Diarrhoea b, Loose stools Hepatic enzyme increased Bronchospasm Nausea, Vomiting Pancreatitis b, Stomatitis, Glossitis Gall bladder precipitation b, Kernicterus Skin and subcutaneous tissue disorders Rash Pruritus Urticaria Stevens Johnson Syndrome b, Toxic epidermal necrolysis b, Erythema multiforme, Acute generalised exanthematous pustulosis Renal and urinary disorders Haematuria, Glycosuria Oliguria, Renal precipitation ( reversible) General disorders and administration site conditions Phebitis, Injection site pain, Pyrexia Oedema, Chills Investigations Blood creatinine increased Coombs test false positive b, Galactosaemia test false positive b Non enzymatic methods for glucose determination false positive b a Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. b See section 4.4 Description of selected adverse reactions Infections and infestations Reports of diarrhoea following the use of ceftriaxone may be associated with Clostridium difficile. Appropriate fluid and electrolyte management should be instituted (see section 4.4). 12

13 Ceftriaxone-calcium salt precipitation Rarely, severe, and in some cases, fatal, adverse reactions have been reported in pre-term and full-term neonates (aged < 28 days) who had been treated with intravenous ceftriaxone and calcium. Precipitations of ceftriaxonecalcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in neonates is a result of their low blood volume and the longer half-life of ceftriaxone compared with adults (see sections 4.3, 4.4, and 5.2). Cases of renal precipitation have been reported, primarily in children older than 3 years of age and who have been treated with either high daily doses (e.g. 80 mg/kg/day) or total doses exceeding 10 grams and who presented with other risk factors (e.g. fluid restrictions or confinement to bed). The risk of precipitate formation is increased in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may lead to renal insufficiency and anuria, and is reversible upon discontinuation of ceftriaxone (see section 4.4). Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, primarily in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitation with intravenous application - above 30 % in some studies. The incidence appears to be lower with slow infusion (20-30 minutes). This effect is usually asymptomatic, but the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting in rare cases. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone (see section 4.4). 4.9 Overdose In overdose, the symptoms of nausea, vomiting and diarrhoea can occur. Ceftriaxone concentrations cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdose should be symptomatic 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antibacterials for systemic use, Third-generation cephalosporins, ATC code: J01DD04. Mode of action Ceftriaxone inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death. Resistance Bacterial resistance to ceftriaxone may be due to one or more of the following mechanisms: hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), carbapenemases and Amp C enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species. reduced affinity of penicillin-binding proteins for ceftriaxone. outer membrane impermeability in Gram-negative organisms. bacterial efflux pumps. 13

14 Susceptibility testing breakpoints Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows: Pathogen Dilution Test (MIC, mg/l) Susceptible Resistant Enterobacteriaceae 1 > 2 Staphylococcus spp a. a. Streptococcus spp. ( Groups A, B, C and G) b. b. Streptococcus pneumoniae 0.5 c > 2 Viridans group Streptococci 0.5 > 0.5 Haemophilus influenzae 0.12 c > 0.12 Moraxella catarrhalis 1 > 2 Neisseria gonorrhoeae 0.12 > 0.12 Neisseria meningitidis 0.12 c > 0.12 Non-species related 1 d > 2 a. Susceptibility inferred from cefoxitin susceptibility. b. Susceptibility inferred from penicillin susceptibility. c. Isolates with a ceftriaxone MIC above the susceptible breakpoint are rare and, if found, should be retested and, if confirmed, should be sent to a reference laboratory. d. Breakpoints apply to a daily intravenous dose of 1 g x 1 and a high dose of at least 2 g x 1 Clinical efficacy against specific pathogens The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of ceftriaxone in at least some types of infections is questionable. Commonly susceptible species Gram -positive aerobes Staphylococcus aureus (methicillin-susceptible) Staphylococci coagulase-negative (methicillin-susceptible) Streptococcus pyogenes (Group A) Streptococcus agalactiae (Group B) Streptococcus pneumoniae Viridans Group Streptococci 14

15 Gram-negative aerobes Borrelia burgdorferi Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis Neisseria gonorrhoea Neisseria meningitidis Proteus mirabilis Providencia spp. Treponema pallidum Species for which acquired resistance may be a problem Gram-positive aerobes Staphylococcus epidermidis + Staphylococcus haemolyticus + Staphylococcus hominis + Gram-negative aerobes Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli % Klebsiella pneumoniae % Klebsiella oxytoca % Morganella morganii Proteus vulgaris Serratia marcescens Anaerobes Bacteroides spp. Fusobacterium spp. Peptostreptococcus spp. Clostridium perfringens Inherently resistant organisms Gram-positive aerobes Enterococcus spp. Listeria monocytogenes 15

16 Gram-negative aerobes Acinetobacter baumannii Pseudomonas aeruginosa Stenotrophomonas maltophilia Anaerobes Clostridium difficile Others: Chlamydia spp. Chlamydophila spp. Mycoplasma spp. Legionella spp. Ureaplasma urealyticum All methicillin-resistant staphylococci are resistant to ceftriaxone. + Resistance rates >50% in at least one region % ESBL producing strains are always resistant 5.2 Pharmacokinetic properties No pharmacokinetic data are available for Ceftriaxone as sodium) 500mg powder for injection, as it is regarded as qualitatively essentially the same as the innovator product Rocephin 500mg powder for solution for Injection (Roche Products Ltd, U.K). Absorption After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg and 1 g, the plasma ceftriaxone levels are approximately 80 and 150 mg/l respectively. Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g is about 81 mg/l and is reached in 2-3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose. Distribution The volume of distribution of ceftriaxone is 7 12 l. Concentrations well above the minimal inhibitory concentrations of most relevant pathogens are detectable in tissue including lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone, and in cerebrospinal, pleural, prostatic and synovial fluids. An 8-15 % increase in mean peak plasma concentration (Cmax) is seen on repeated administration; steady state is reached in most cases within hours depending on the route of administration. 16

17 Penetration into particular tissues Ceftriaxone penetrates the meninges. Penetration is greatest when the meninges are inflamed. Mean peak ceftriaxone concentrations in CSF in patients with bacterial meningitis are reported to be up to 25 % of plasma levels compared to 2 % of plasma levels in patients with uninflamed meninges. Peak ceftriaxone concentrations in CSF are reached approximately 4-6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is excreted in the breast milk at low concentrations (see section 4.6). Protein binding Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/l. Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/l). Biotransformation Ceftriaxone is not metabolised systemically; but is converted to inactive metabolites by the gut flora. Elimination Plasma clearance of total ceftriaxone (bound and unbound) is ml/min. Renal clearance is 5-12 ml/min % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours. Patients with renal or hepatic impairment In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered with the half-life slightly increased (less than two fold), even in patients with severely impaired renal function. The relatively modest increase in half-life in renal impairment is explained by a compensatory increase in nonrenal clearance, resulting from a decrease in protein binding and corresponding increase in non-renal clearance of total ceftriaxone. In patients with hepatic impairment, the elimination half-life of ceftriaxone is not increased, due to a compensatory increase in renal clearance. This is also due to an increase in plasma free fraction of ceftriaxone contributing to the observed paradoxical increase in total drug clearance, with an increase in volume of distribution paralleling that of total clearance. Older people In older people aged over 75 years the average elimination half-life is usually two to three times that of young adults. Paediatric population The half-life of ceftriaxone is prolonged in neonates. From birth to 14 days of age, the levels of free ceftriaxone may be further increased by factors such as reduced glomerular filtration and altered protein binding. During childhood, the half-life is lower than in neonates or adults. The plasma clearance and volume of distribution of total ceftriaxone are greater in neonates, infants and children than in adults. 17

18 Linearity/non-linearity The pharmacokinetics of ceftriaxone are non-linear and all basic pharmacokinetic parameters, except the elimination half-life, are dose dependent if based on total drug concentrations, increasing less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone but not for free (unbound) ceftriaxone. Pharmacokinetic/pharmacodynamic relationship As with other beta-lactams, the pharmacokinetic-pharmacodynamic index demonstrating the best correlation with in vivo efficacy is the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftriaxone for individual target species (i.e. %T > MIC). 5.3 Preclinical safety data There is evidence from animal studies that high doses of ceftriaxone calcium salt led to formation of concrements and precipitates in the gallbladder of dogs and monkeys, which proved to be reversible. Animal studies produced no evidence of toxicity to reproduction and genotoxicity. Carcinogenicity studies on ceftriaxone were not conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients None. 6.2 Incompatibilities Based on literature reports, ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole and aminoglycosides. Solutions containing ceftriaxone should not be mixed with or added to other agents except those mentioned in section 6.6. In particular diluents containing calcium, (e.g. Ringer s solution, Hartmann s solution) should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Ceftriaxone must not be mixed or administered simultaneously with calcium containing solutions including total parenteral nutrition (see section 4.2, 4.3, 4.4 and 4.8). 6.3 Shelf life 36 months For shelf life of diluted product see section Special precautions for storage Undiluted vials: Do not store above 25 C. Protect from light. Single use vials. Discard unused portion. 18

19 For storage conditions of diluted product see section Nature and contents of container Type II glass vials with grey bromobutyl stoppers then capsulated with aluminium pilfer-proof caps. Ceftriaxone (as sodium) 500mg vial for injection is available in packs of 1 vial. 6.6 Instructions for use and handling and disposal From a microbiological point of view, the product should be used immediately after reconstitution and dilution. If the product is not used immediately, in-use storage times and conditions are the responsibility of the user. The use of freshly prepared solutions is recommended. These maintain potency for at least 6 hours at or below 25 C in daylight, or 24 hours at refrigerator at 2 C -8 C. The medicinal product should be reconstituted before administration to the patient. The volume of diluent to be used for the reconstitution is dependent upon the method of administration. The reconstituted solution should be shaken up to 2 minutes to ensure complete dissolution of ceftriaxone. The reconstitution/dilution is to be made under aseptic conditions. The reconstituted solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles. Intramuscular injection: 500mg Ceftriaxone should be dissolved in 3.5ml of 1.06% Lidocaine Hydrochloride solution. The solution should be administered by deep intramuscular injection. Intravenous injection : 500mg Ceftriaxone should be dissolved in 10 ml of Water for Injections. The injection should be administered over 5 minutes, directly into the vein or via the tubing of an intravenous infusion. When reconstituted for intravenous injection, the white to yellowish crystalline powder gives a pale yellow solution. Intravenous infusion: 500mg Ceftriaxone should be dissolved in 20ml of one of the following calcium-free solutions: Dextrose Injection 5% or 10%, Sodium Chloride Injection, Sodium Chloride and Dextrose Injection ( 0.45% Sodium Chloride and 2.5% Dextrose), Dextran 6% in Dextrose Injection 5%, Hydroxyethyl Starch 6-10% infusions. The infusion should be administered over at least 30 minutes. Concentration for the intravenous injection: 100mg/ml Concentration for the intravenous infusion: 50mg/ml For single use only. Any unused product or waste material should be disposed of in accordance with local requirements. 7. SUPPLIER Egyptian International Pharmaceutical Industries Co. (EIPICO) Tenth of Ramadan City- Industrial Area B1- Egypt P.O. Box: 149 Tenth of Ramadan Telephone: Fax:

20 8. WHO REFERENCE NUMBER (PREQUALIFICATION PROGRAMME) 9. DATE OF FIRST PREQUALIFICATION/RENEWAL OF PREQUALIFICATION 16 May DATE OF REVISION OF THE TEXT May 2016 References General reference sources for this SmPC include: Summary of product characteristics for Rocephin Injection: Summary of product characteristics for Ceftriaxone 0.5g Powder for Solution for Injection: 20